Therapy for neoplastic disease has largely involved the use of radiation, surgery and chemotherapeutic agents. However, these treatments, while beneficial in some cases, have marginal or no effect in many others. Furthermore, these approaches often have unacceptable toxicity. In cases where the cancer has become metastatic, there is often no effective curative treatment.
Specificity is a major problem with most anticancer agents. Ideally, anticancer agents would discriminate between host cells that are cancerous and host cells that are not cancerous. However, most anticancer drugs are indiscriminate at this level and generally target actively multiplying cells. Among the consequences are immunosuppression and disruption of hematopoiesis, epithelial tissues (e.g., intestinal mucosa) and the reproductive system.
Heat shock proteins (Hsps) were originally observed to be expressed in increased amounts in mammalian cells which were suddenly exposed to sudden elevations in temperature. Further experiments demonstrated that such proteins are produced in response to various types of stress, including, for example, glucose deprivation. The family of heat shock proteins further includes homologous proteins that are constitutively expressed. For example, whereas Hsp70 is not expressed at normal temperatures, a constitutively expressed heat shock protein cognate (Hsc70) participates in protein translocation across membranes and other functions. Most heat shock proteins are referred to as “molecular chaperones” in that they bind and stabilize proteins in their non-native states. For example, Hsps bind to nascent peptides emerging from ribosomes or extruded into the endoplasmic reticulum, at intermediate stages of folding, and assembly.
It has been observed that Hsps prepared from tumors in experimental animals are able to induce immune responses in a tumor specific manner. Evidence suggests that immunity is not conferred by the Hsp per se, but by peptides complexed with the Hsp.
Although autologous tumor-derived Hsp-peptide complexes are capable of eliciting an immune response against cells of the same tumor, there are drawbacks to use of such autologous complexes in vaccines for cancer treatment. For example, each patient would require a personalized or custom vaccine. To prepare such a vaccine, it would be necessary to provide Hsp preparations from a patients own tumor. Furthermore, ensuring availability of sufficient Hsp preparations would necessitate culture of the tumor tissue are required and Hsp preparations from such tumors are low. Although peptides might be synthesized and complexed with Hsps in vitro, attempts to identify peptides of interest complexed with Hsps have generally been unsuccessful. Consequently, significant clinical constraints are imposed with regard to the manufacture of Hsp-peptide preparations.